Transplants of pluripotent hematopoietic stem cells (PHSC) or bone marrow are an effective immunotherapy against hematological malignancies. However, graft-versus-host disease (GvHD) remains a major source of morbidity and mortality following transplant. GvHD is a systemic immunological disorder that develops when donor immune cells attack not just residual tumor cells, but also normal host tissue, particularly the skin, liver, and gastro-intestinal tract. GvHD is traditionally divided into two groups: acute (aGvHD), which arises before the 100 day mark post-transplant, and chronic (cGvHD), which occurs after 100 days post-transplant; however, the current consensus is that clinical manifestations and not time after transplantation determine whether the clinical syndrome is considered aGvHD or cGvHD. While mild aGvHD (grade I or II) is associated with little morbidity and almost no mortality, higher grades (III and IV) are associated with very high mortality rates.
Currently available diagnostic and staging tools frequently fail to identify those at higher risk of GvHD development, morbidity, treatment unresponsiveness and death. A number of candidate aGvHD biomarkers are currently under active investigation as promising diagnostic and prognostic tools, but to the inventors' knowledge none have yet been validated in multicenter prospective trials. Prior art describing such biomarkers includes U.S. Pat. No. 8,637,232 (disclosing biomarkers predicting, among other things, GvHD in lung transplant patients); U.S. Pat. Nos. 8,603,754; 8,153,130; and 7,763,425. The prior art also includes following articles: S. Paczesny, Discovery and validation of graft-versus-host disease biomarkers, Blood vol. 121 no. 4 pp. 585-594 (2013); M. T. Vander Lugt et al., ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death, NEJM vol. 369 no. 6 pp. 529-539 (2013); E. Weissinger et al., Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, Blood vol. 109 no. 12 pp. 5511-5519 (2007); G. Socié, Graft-versus-host disease: proteomics comes of age, Blood vol. 113 no. 2 p. 271-272 (2009); S. Paczesny et al., Blood vol. 113 no. 2 pp. 273-278 (2009); Y-B Chen et al., Biomarkers for acute GVHD: can we predict the unpredictable? Bone Marrow Transplantation vol. 48 pp. 755-760 (2013); R. Srinivasan et al., Accurate diagnosis of acute graft-versus-host disease using serum proteomic pattern analysis, Experimental Hematology vol. 34 pp. 796-801 (2006); S. Paczesny et al., Graft-versus-Host Disease Biomarkers: Omics and Personalized Medicine, Int. J. Hematol. vol. 98 no. 3 pp. 275-292 (2013). J. Levine et al., Clinical applications for biomarkers of acute and chronic graft-versus-host disease, Biol. Blood Marrow Transplan. vol. 18 (1 Suppl): S116-S124 (2012); M. Cuzzola et al., A molecular and computational diagnostic approach identifies FOXP3, ICOS, CD52 and CASP1 as the most informative biomarkers in acute graft-versus-host disease, Haematologica vol. 97 no. 10 pp. 1532-1538 (2012), J. Rozmus et al., Biomarkers in Chronic Graft-versus-Host Disease, Expert Rev. Hematol. vol. 4 no. 3 pp. 329-342 (2011); J. Levine et al., Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood, vol. 119 no. 16 pp. 3854-3860 (2012). The Srinivasan et al. paper describes SELDI-TOF-based proteomic analysis as a rapid and accurate method to diagnose aGvHD and is considered the closest known prior art.
Clinical tests predictive of the development of aGvHD and cGvHD (either de novo or secondary to aGvHD), as well as tests predicting the severity of the disease (both acute and chronic) would be of great interest, because they could guide therapeutic decisions towards more or less aggressive treatment. The present invention meets that need.